It is now well-established that HIV-1 infection causes a slow but progressive impairment of the immune system and that a relentless destruction of CD4+ T cells represents another hallmark of HIV-1 infection.
HIV-1 uses primarily dendritic cells (DC) to penetrate the mucosal epithelium1, 2. The virus is then transferred and disseminated from this entry site3 to T-cell zones in secondary lymphoid organs, where it can productively infect CD4+ T cells. The infection causes depletion of CD4+ T cells4, 5, progressive impairment of the immune system, as well as chronic hyperactivation of both CD4+ and CD8+ T cells4, 6, 7.
The initial attachment step of HIV-1 to DCs may occur through several interactions between the virus and the target cell surface (reviewed in8, 9). Recently, it was shown that the dendritic cell immunoreceptor (DCIR) can behave as an attachment factor for HIV-118. This association results in trans infection of CD4+ T cells13-17. DCIR also contributes to cis-infection, that is, infection of surrounding CD4+ T cells by virions produced by DCs productively infected with HIV-1. It has also been shown that multiples isoforms of DCIR exists22 and that the neck domain of the transmembrane isoform is important for HIV-1 binding and infection of DCs18.
Phosphorylation and dephosphorylation are amongst the most important post-translational protein modifications often resulting in major changes in protein function and cellular function. Although it is known that of DCIR contains a ITIM domain and that phosphorylation of the ITIM domain plays an important role in the function of the receptor25,26, nothing is known about the recruitment of the phosphatases or tyrosine kinases (TKs) after HIV-1 attachment to DCIR. Therefore, the precise contribution of DCIR-mediated intracellular signal transducers in virus capture, transfer and infection remains unknown and there is a particular need for compounds and method that would target one or more DCIR intracellular signalling events triggered following a physical interaction between DCIR and a virus particle.
Therefore, there is a need for the prevention and treatment of virus infections in subjects, more particularly in humans infected with or susceptible of HIV-1 infection. There is also a need for methods, compounds and pharmaceutical compositions for inhibiting dendritic cell immunoreceptor (DCIR) signalling in a mammalian cell.